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HLA-Ehigh /HLA-Ghigh /HLA-IIlow Human iPSC-Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration
Yi-Hsien Fang1,2, Saprina P H Wang2,3, I-Chuang Liao4
1Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan.
Insights
Hypoimmunogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with high HLA-E/HLA-G and low HLA-II expression show immune privilege. These cells successfully repaired infarcted hearts and improved cardiac function in rats, offering a promising platform for regenerative medicine.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Immunology
Background:
- Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) show therapeutic potential for heart repair.
- Allogeneic transplantation of hPSC-CMs faces significant rejection due to human leukocyte antigen (HLA) mismatching.
- Developing hypoimmunogenic hPSCs is critical for successful allogeneic cell therapy.
Purpose of the Study:
- To demonstrate the immune privilege and therapeutic efficacy of specific HLA-engineered human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
- To evaluate the in vivo survival and function of HLA-Ehigh/HLA-Ghigh/HLA-IIlow hiPSC-CMs in a rat myocardial infarction model.
- To investigate the underlying immune evasion mechanisms of these modified hiPSC-CMs.
Main Methods:
- Induction of transmural myocardial infarction in rats via ischemia-reperfusion surgery.
- Intramyocardial injection of different types of hPSC-CMs, including HLA-Ehigh/HLA-Ghigh/HLA-IIlow hiPSC-CMs, at 4 days post-infarct.
- Treatment with a very low dose of cyclosporine A (CsA).
- Assessment of cell survival, cardiac function, infarct size, and immune cell activation (NK cells, cytotoxic T cells).
Main Results:
- Only HLA-Ehigh/HLA-Ghigh/HLA-IIlow hiPSC-CMs survived and improved cardiac function with reduced infarct size in CsA-treated rats.
- These modified hiPSC-CMs activated the SHP-1 signaling pathway in natural killer (NK) and cytotoxic T cells, evading immune attack.
- The cells demonstrated effective myocardial repair and functional recovery at clinically relevant CsA doses.
Conclusions:
- HLA-Ehigh/HLA-Ghigh/HLA-IIlow hiPSC-CMs possess immune privilege, enabling successful allogeneic transplantation.
- These engineered hiPSC-CMs represent a promising cell source for cardiac regeneration medicine.
- Targeting HLA expression can overcome immune barriers in stem cell-based therapies for heart disease.
Abstract:
Although human pluripotent stem cells (hPSCs)-derived cardiomyocytes (hPSC-CMs) can remuscularize infarcted hearts and restore post-infarct cardiac function, post-transplant rejection resulting from human leukocyte antigen (HLA) mismatching is an enormous obstacle. It is crucial to identify hypoimmunogenic hPSCs for allogeneic cell therapy. This study is conducted to demonstrate the immune privilege of HLA-Ehigh /HLA-Ghigh /HLA-IIlow human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs). Ischemia-reperfusion surgery is done to create transmural myocardial infarction in rats. At post-infarct 4 days, hPSC-CMs (1.0×107 cells per kg), including human embryonic stem cell-derived cardiomyocytes (hESC-CMs), HLA-Elow/HLA-Glow/HLA-IIhigh hiPSC-CMs, and HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs, are injected into the infarcted myocardium. Under the treatment of very low dose cyclosporine A (CsA), only HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs survive in vivo and improved post-infarct cardiac function with infarct size reduction. HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs activate the SHP-1 signaling pathway of natural killer (NK) cells and cytotoxic T cells to evade attack by NK cells and cytotoxic T cells. Herein, it is demonstrated that using a clinically relevant CsA dose, HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs repair the infarcted myocardium and restore the post-infarct heart function. HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSCs are less immunogenic and may serve as platforms for regeneration medicine.
